To mount effective immune responses against invading pathogens, CD4+ helper T (Th) cells have to produce high levels of inflammatory cytokines, including IFN-? and TNF-a, but simultaneously suppress the expression of anti-inflammatory cytokines, such as IL-10. However, dysregulated Th responses can also lead to organ-specific autoimmune diseases, such as autoimmune diabetes, multiple sclerosis, and Crohn's disease. Enhancing the production of IL-10 and suppressing the expression of IFN-? and TNF-a by Th cells have been shown to be therapeutic for such autoimmune diseases. Thus, manipulating the cytokine production by Th cells has emerged as a novel treatment for both infectious and autoimmune diseases and has been a long-term objective of our research. We recently discovered that the transcription factor Ets-1 reciprocally regulated the production of inflammatory and anti-inflammatory cytokines in Th cells, and was essential for mounting IFN-? and TNF-a-mediated Th inflammatory responses. In addition, Ets-1 underwent phosphorylation and was shuttled between the nucleus and cytoplasm in activated Th cells, indicating the function of Ets-1 is regulated at multiple levels. Therefore, Ets-1 appears to be an ideal target for manipulating Th immune responses and bears great therapeutic potential. In this grant proposal, we plan to further investigate the mechanism of action of Ets-1. We are particularly interested in understanding the regulation and functional significance of phosphorylation and nuclear/cytoplasm translocation of Ets-1. The knowledge gained from the proposed experiments will allow us to develop feasible approaches to influence the function of Ets-1 and eventually lead to novel treatments of infectious and autoimmune diseases. [unreadable] [unreadable]